|Year : 2013 | Volume
| Issue : 1 | Page : 2-3
New drug discovery: Where are we heading to?
Department of Pharmacy, Faculty of Technology and Engineering, Kalabhavan, The M S University of Baroda, Vadodara, Gujarat - 390 001, India
|Date of Web Publication||20-Feb-2013|
M R Yadav
Department of Pharmacy, Faculty of Technology and Engineering, Kalabhavan, The M S University of Baroda, Vadodara, Gujarat - 390 001
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Yadav M R. New drug discovery: Where are we heading to?. J Adv Pharm Technol Res 2013;4:2-3
When we look back at our past records about discovering new drugs, it is dismal and pathetic. Leave aside the past, the future does not seem to be rosy considering the present conditions. As a growing world economy, are we doing enough in this direction? Future's seeds are always sown in the past. Have we done enough or are we still doing enough to be optimistic of a new era where India would be a fountain head of innovations? There are so many questions which need to be answered. A critical analysis of the past and the present becomes pertinent to get answers of these questions.
New drug discovery is a complex process involving the inputs of many branches of science like, physical and organic chemistry, cellular and molecular biology, biochemistry, pharmacology, computational chemistry, and so on and so forth. Discovering a new drug molecule and bringing it to the clinician's desk requires team efforts of so many experts in their own field. When we peep into the past we notice that new drugs have been discovered either serendipitously or by keen observations and systematic studies. Upto 1980s the rate of launching new drug molecules per year has remained impressive but 1990 onwards this rate has decreased dramatically. Medicinal chemists became more rational in their approach in the later years for discovering new drugs and that should have increased the rate of discovering new drug molecules over the years. But astonishinglythe reverse has happened. One understandable reason is a stricter regulatory regime which is more sensitive to the reporting of side effects of the new drugs and providing of exhaustive pre-clinical and clinical data. The other reason scientists quote is the lack of information about new disease targets. Hype was created about human genome mapping that once completed this would provide immense amount of information about new biological targets for discovering new drug molecules. Alas!this has not happened. There is no denying the fact that fewer drugs are getting discovered across the globe, but what is the situation in our country?
Free India took its first breath in the lap of utter poverty. Even food and other essential commodities were not available to its people leave aside medicines. To provide essential drugs at cheaper rates to the people, Government of India enacted a legislation, the Indian Patent Act, in 1970. According to this Act "Product Patenting" was not tenable as this Act recognized only the "Process Patenting." This Act proved to be a boon for the growth of pharmaceutical industry in the country. By modifying the processes for the active pharmaceutical ingredient APIs as well as the formulations, medicines could be offered to the poor populace at affordable prices. Pharmaceutical industry grew by leaps and bounds and India became an exporting country of pharmaceuticals even to the Western countries.
Unfortunately, this legislation which catalyzed the growth of pharmaceutical industry and provided medicines at affordable rates to the poor people, proved to be a big stumbling block in the new drug discovery process for the nascent pharmaceutical industry. It crippled the basic research in pharmaceutical field and forced us to become copycats. By adopting reverse engineering we could make any molecule in the world by modifying the process. This proved to be a death knell for our basic research. When a new drug molecule was available at the least price by slight modification of the available synthetic process then why would anybody spend fortunes in discovering new drug molecules? Apart from this main reason, lack of team work is another factor why we are not succeeding even now in our efforts. But, is discovery of new drug molecules such a cumbersome resource and time consuming process that it seems to be a dream for us? That too, when we are ushering into an era, which the whole world says, belongs to India and China. To my mind, discovering a new drug entity is not as difficult and unachievable a task as it is being projected. May be we are being misled by certain forces with ulterior motives and selfish interests so that we do not make serious efforts in this direction.
As mentioned earlier new drug discovery requires team work. We do not know when we will start working as a team. Another misconception people have is about computer aided drug designing or molecular modeling. People think that drug designing techniques will provide new drug molecules without efforts. This has not happened till date even after implementation of these techniques for the last 10-15 years. And this will not happen in near future also. Computer aided drug designing techniques are lead optimization techniques and in some cases hasten the process of lead identification. These techniques are used to make the drug discovery process more rational. On their own these will never discover a new drug. But yes, these techniques save a lot of time and energy and provide us a better understanding of the discovery process. There are many techniques which are part of computer aided drug designing process. To start with the simplest one is Quantitative structure-activity relationship (QSAR) which is also referred to as 2D-QSAR sometimes. 3D-QSAR involving Comparative Molecular Field Analysis (CoMFA) and Comparative molecular similarity index analysis (CoMSIA) are extension of QSAR. QSAR is not able to take the three dimensional structure of a molecule into consideration due to absence of three-dimensional parameterization of structures. 3D-QSAR scores over QSAR in this respect. Docking studies throw more light on the binding modes of drugs with their target proteins but it is feasible only when the crystal structure of the target enzyme/protein is known with good resolution. Docking studies are also used for virtual screening of databases. But the ideal technique for virtual screening of compounds is through pharmacophore mapping and screening, especially when the structure of the target is not known. Very large databases can be first screened by pharmacophorebecause the technique is quite fast followed by screening of the positive hits using docking studies. Insilico designing of novel compounds can also be performed using deNovo designing techniques subject to the condition that the target structure in known.
Drug discovery scenario has completely changed in the last decade. Earlier, a lot of emphasis used to be put in discovering more potent compounds with fewer side effects using animal models. When such compounds were entering the clinical phase, these used to face a high rejection rates due to absorption, distribution, metabolism, excretion and toxicity (ADMET) problems thereby putting huge efforts and resources down the drain. Nowadays more emphasis is on assessing new chemical entities for ADMET parameters prior to further studies. Several software are available to theoretical assessing of ADMET parameters for a new chemical entity. In a typical situation when a new chemical entity shows good binding affinity with the target enzyme/receptor, it is assessed for its ADMET parameters followed by whole body autoradiography. Further biological evaluations are performed only when the compound passes these litmus tests.
It is a pity that majority of our researchers in the field are unaware about these techniques. We are not making serious efforts to train our graduate students in these techniques. There is a need to give enmass training to our researchers on computer aided designing techniques. In 1980s several groups were working in the field of QSAR in Pharmacy institutions in India. Those days the number of pharmacy education imparting institutions were also limited, may be 20-25 at the most. Today, there are about a thousand such institutions but the number of research groups engaged in new drug discovery can be counted on fingers. And how many of these research groups are using computer-aided designing tools? The figure has awfully deteriorated. Where are we heading to? Have we put ourselves in a reverse gear?
| Authors|| |
Prof. (Dr.) M. R. Yadav